The invention relates generally to the field of mobilization and recruitment of stem cells and progenitor cells.
Recruitment of stem cells and/or progenitor cells are important in a variety of applications. Vasculogenesis, which involves the growth of vessels derived from endothelial progenitor cells, is an example of such a process. Vasculogenesis, as well as angiogenesis, the process by which new blood vessels are formed from extant capillaries, and the factors that regulate these processes, are important in embryonic development, inflammation, and wound healing, and also contribute to pathologic conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis, and chronic inflammatory diseases (see, e.g., U.S. Pat. No. 5,318,957; Yancopoulos et al. (1998) Cell 93:661-4; Folkman et al. (1996) Cell 87;1153-5; and Hanahan et al. (1996) Cell 86:353-64).
Both angiogenesis and vasculogenesis involve the proliferation of endothelial cells. Endothelial cells line the walls of blood vessels; capillaries are comprised almost entirely of endothelial cells. The angiogenic process involves not only increased endothelial cell proliferation, but also comprises a cascade of additional events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane. Vasculogenesis involves recruitment and differentiation of mesenchymal cells into angioblasts, which then differentiate into endothelial cells which then form de novo vessels (see, e.g., Folkman et al. (1996) Cell 87:1153-5).
Several angiogenic and/or vasculogenic agents with different properties and mechanisms of action are well known in the art. For example, acidic and basic fibroblast growth factor (FGF), transforming growth factor alpha (TGF-xcex1) and beta (TGF-xcex2), tumor necrosis factor (TNF), platelet-derived growth factor (PDGF), vascular endothelial cell growth factor (VEGF), and angiogenin are potent and well-characterized angiogenesis-promoting agents. In addition, both nitric oxide and prostaglandin (a prostacyclin agonist) have been shown to be mediators of various angiogenic growth factors, such as VEGF and bFGF. However, the therapeutic applicability of some of these compounds, especially as systemic agents, is limited by their potent pleiotropic effects on various cell types.
Angiogenesis and vasculogenesis have been the focus of intense interest since these processes can be exploited to therapeutic advantage. Stimulation of angiogenesis and/or vasculogenesis can aid in the healing of wounds, the vascularizing of skin grafts, and the enhancement of collateral circulation where there has been vascular occlusion or stenosis (e.g., to develop a xe2x80x9cbiobypassxe2x80x9d around an obstruction due to coronary, carotid, or peripheral arterial occlusion disease). In addition, identification of agents that can stimulate recruitment of stem cells and/or progenitor cells could be useful in the treatment of other conditions associated with cellular injury and/or depletion of cells (e.g., acquired or genetic immune deficiencies). There is an intense interest in factors such agents that are well-tolerated by the subject, but that are of high potency in effecting stimulation of stem cell and/or progentior cell recruitment.
Villablanca ((1998) xe2x80x9cNicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro,xe2x80x9d J. Appl. Physiol. 84:2089-98) studied the effects of nicotine on endothelial DNA synthesis, DNA repair, proliferation, and cytoxicity using cultures of bovine pulmonary artery endothelial cells in vitro.
The reference Carty et al. ((1996) xe2x80x9cNicotine and cotinine stimulate secretion of basic fibroblast growth factor and affect expression of matrix metalloproteinases in cultured human smooth muscle cells,xe2x80x9d J Vasc Surg 24:927-35) demonstrate that nicotine stimulates vascular smooth muscle cells to produce fibroblast growth factor, and also upregulates the expression of several matrix metalloproteinases. The investigators propose that these data demonstrate mechanisms by which smoking may cause atherosclerosis and aneurysms.
The reference by Belluardo et al. ((1998) Acute intermittent nicotine treatment produces regional increases of basic fibroblast growth factor messenger RNA and protein in the tel-and diencephalon of the rat,xe2x80x9d Neuroscience 83:723-40) reported that nicotine stimulates the expression of fibroblast growth factor-2 in rat brain, which the investigators propose may explain the neuroprotective effect of nicotine in the rat brain.
Moffett et al. ((xe2x80x9cIncreased tyrosine phosphorylation and novel cis-actin element mediate activation of the fibroblast growth factor-2 (FGF-2) gene by nicotinic acetylcholine receptor. New mechanism for trans-synaptic regulation of cellular development and plasticity,xe2x80x9d Mol Brain Res 55:293-305) report that nicotine stimulates the expression of fibroblast growth factor-2 in neural crest-derived adrenal pheochromatocytes utilizing a unique transcriptional pathway that requires tyrosine phosphorylation. The authors propose that these findings suggest that activation of nicotine receptors may be involved in neural development.
Cucina et al. ((1999) xe2x80x9cNicotine regulates basic fibroblastic growth factor and transforming growth factor xcex21 production in endothelial cells,xe2x80x9d Biochem Biophys Res Commun 257:302-12) report that nicotine increases the release of bFGF, decreases the release of TGF 1 from endothelial cells, and increases endothelial mitogenesis. The authors conclude that these effects may have a key role in the development and progression of atherosclerosis.
Volm et al. (1999) xe2x80x9cAngiogenesis and cigarette smoking in squamous cell lung carcinomas: an immunohistochemical study of 28 cases.xe2x80x9d Anticancer Res 19(1A):333-6 reports that angiogenesis in lung tumors is linked to a patient""s smoking habits.
Macklin et al. (1998) xe2x80x9cHuman vascular endothelial cells express functional nicotinic acetylcholine receptors,xe2x80x9d J. Pharmacol. Exper. Therap. 287:435-9 reports that endothelial cells express both functional nicotinic (neuronal type) and muscarinic acetylcholine receptors.
U.S. Pat. Nos. 5,318,957; 5,866,561; and 5,869,037 describe use of various compounds (haptoglobin and estrogen) and methods (adenoviral-mediated gene therapy of adipocytes) to effect angiogenesis.
For recent reviews in the field of angiogenesis and vasculogenesis, see, e.g., Yancopoulos et al. (1998) Cell 93:661-4; Folkman et al. (1996) Cell 87;1153-5; and Hanahan et al. (1996) Cell 86:353-64.
The present invention features methods for recruitment of bone marrow-derived stem cells (e.g., endothelial cell precursors, hematopoietic stem cells) by administration of nicotine or other nicotine receptor agonist. The methods of the invention can be used in, for example, treatment of conditions amenable to treatment by recruitment of bone marrow-derived stem cells (e.g., neutropenia).
One object of the present invention to provide a method of recruiting endothelial progenitor cells to enhance angiogenesis.
Another object of the present invention is to provide a method of treating and preventing diseases and ailments involving tissue damage (e.g., to facilitate cellular repair), such as in myocardial and cerebral infarctions, mesenteric or limb ischemia, wounds, and vascular occlusion or stenosis.
Another object of this invention is to provide a method of accelerating wound healing, vascularization and incorporation of skin grafts, musculocutaneous flaps or other surgically transplanted tissues; or to enhance the healing of a surgically created anastomosis.
Another object of the invention is provide a method of treating conditions or diseases associated with depletion of cells that develop from bone marrow-derived stem cells (e.g., immune cells, e.g., neutrophils, eosinophils, T cells, B cells, macrophages, natural killer cells, and the like).
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the methods of the invention and compositions used therein as more fully described below.